Inhalation therapy has been applied for treatment of lung and respiratory tract disease, diagnosis of disease, transrespiratory tract and transpulmonary whole body medication, prophylaxis of disease, transrespiratory tract immunity desensitization therapy, etc. as a medicinal use of transrespiratory. However, the adaptation-determining method of this therapy is fully examined at neither of the cases. Therefore, development of the corresponding respirable formulation is desired.
As features of a general respirable formulation, recognized are 1) quick expression of drug effects, 2) gradual reduction of side effects, 3) possibility of small dose administration, 4) avoidance of the first-pass effect, etc. When a target region is lung, the respirable formulation is equipped with further outstanding features by having a large surface area equal to small intestine. In applying the respirable formulation as a targeting therapy, it is necessary to consider a selection-criteria method of the respirable formulation from viewpoint of not only efficacy to disease but a generation method of medicine particles, arrival parts, and relevancy of the basic physical properties of medicine to them. Now, the respirable formulation is used for bronchodilator, mucosa solubilizer, antibiotic, antiallergic agent, steroid, vaccine, physiological saline, etc., and in the case of their clinical application, site of action of inhalant, mechanism of the action, composition, direction for use, etc. are considered to be of important factors.
Recent years, in treatment of bronchial asthma or chronic lung disease, a Dry Powder Inhaler (Dry Powder Inhaler, DPI) has come to attract attention. This form has advantage that, in addition of the feature as above-mentioned respirable formulation, medicine can be stored with stable form for a long period of time. In DPI, there is a close relationship between a particle diameter of medicine particles being respired by patient and a deposition to respiratory tract [Pharmacia (1997) Vol. 33, No. 6, and 98-102], and the aerodynamics correlation is accepted in what kind of medicine particle diameter deposits inside trachea and lung. Specifically, it is generally known that the optimal sizes of medicine particles which can reach bronchus or lung are particles which have an aerodynamics diameter of about 1 to 6 μm [Int. J. Pharm. (1994) 101 and 1-13].
Preferably, particles of several μm or less reach alveolus, and since they are efficiently absorbed from lung mucosa and migrate into blood, the particle size becomes important. However, the more the particles get fine, the more the fluidity of powder gets worse and, as a result, decline of filling precision and handling property at the time of production gets worried. Then, in order to solve these problems in handling of the DPI formulation, the method mentioned below is well known which mixes micronized particles with coarse particles, such as lactose and erythritol, being used as carrier. According to this method, by making micronized particles adhere to the carrier surface via intermolecular interaction, cohesive force of micronized particles become weaker, and the particle diameter becomes large further as a whole, and thus, the fluidity of the formulation is improved. The other methods including granulation of a medicine and a surface treatment method are mentioned (Patent Document 1).
Here, pirfenidone (henceforth PFD) is the world's first anti-fibrosis agent for approval acquisition to be applied for idiopathic pulmonary fibrosis. The action mechanism is production modulation for various cytokines, such as inflammatory cytokine and anti-inflammation cytokine, and for growth factors which participate in fibrosis formation, and the anti-fibrosis effect is shown based on complex effects, such as fibroblast multiplication depressant action and collagen production depressant action. In comparison between this agent and prednisolone, while prednisolone showed only anti-inflammatory activity, this agent showed both anti-inflammatory activity and anti-fibrosis effect, then, consequently, it is expected that more effective therapeutic results than steroid can be brought about. Although it has been sold since 2008 in Japan, and is widely used for pulmonary fibrosis, many of patients who have taken this agent have showed a side effect of drug-induced photodermatosis, and their expression frequency results in about 60 percent. In order to avoid this problem, suitable dosage form which can easily show effect on lung local part has been desired. However, only oral formulation has been marketed till the present, and more preferable dosage form design aiming at stability and local administration has not been examined irrespective of the high demand. That is, development is desired strongly for new dosage forms which will reduce photodermatosis risk, a side effect of pirfenidone, and will bring about safer pulmonary fibrosis treatment. As DPI formulations in which micronized particles were made to adhere to the carrier surface, a formulation using lactose as a carrier (Patent Document 2), a cyclosporin formulation (Non-patent Document 1), a tranilast formulation (Patent Document 3, Non-patent Documents 2-3), etc. have been reported. However, in any references, the transmigration control to the skin and the photodermatosis risk fall of medicine by the above-mentioned DPI formulation are not described.